Tuesday, May 27, 2008

Matching Tumors to Drugs

A clinical trial offers a first step toward personalizing cancer treatments.

By Courtney Humphries

A genetic match: These CAT scans show the best response to a targeted cancer drug in a lung-cancer patient deemed likely to respond based on a genetic screen. Before treatment (top), the left side of the lung, normally black, is nearly filled with a whitish tumor. After just a month of treatment (bottom), the tumor has shrunk dramatically. Credit: Lecia Sequist

For years, personalized medicine--the concept that treatments could be tailored to a person's unique genetic makeup--has been more buzzword than reality. One of the first diseases expected to benefit from a personalized approach is cancer, which appears in many genetically distinct forms. A new study led by Lecia Sequist, an instructor at Harvard Medical School and an oncologist at Massachusetts General Hospital Cancer Center , offers an initial demonstration that cancer treatment can be tailored to the genetic profile of a patient's tumor. In a small clinical trial published recently in the Journal of Clinical Oncology, patients with lung tumors were genetically screened to identify those likely to respond to a targeted therapy. Those receiving a drug matched to their tumor fared better than is typically seen with standard chemotherapy.

"It's really a giant step forward," says William Pao, a cancer researcher at Memorial Sloane-Kettering Cancer Center, who was not involved in the clinical trial. "The ultimate goal is to take a molecular fingerprint of someone's tumor and assign treatment based on molecular defects."

Standard cancer drugs are designed to preferentially kill cancer cells, but they can still be toxic to normal tissue. But cancer researchers have been working toward the goal of developing an array of drugs that could hit precise molecular targets in tumors, while being less toxic to normal cells. For example, non-small-cell lung cancer is an aggressive form of cancer that is typically treated with chemotherapy; however, in recent years, new drugs for the disease have been developed that target a specific molecule in cancer cells, called the epidermal growth factor receptor (EGFR). The drug examined in this study, Iressa, was the first EGFR inhibitor to come on the market in 2003, but its initial hype fizzled after larger trials showed that it did not lengthen survival for patients in the United States. Currently, EGFR inhibitors are used only after chemotherapy.

Increasingly, scientists have realized that cancers arise from different genetic mutations and have different points of weakness that might vary from person to person. Further research identified specific EGFR mutations in the tumors of a subset of patients that made them more susceptible to EGFR inhibitors. Many scientists have argued that the drugs could provide a greater benefit to these specific patients. In Sequist's trial, which was funded by AstraZeneca, researchers first screened patients with metastatic lung cancer for EGFR mutations and gave those with the mutations the option of receiving Iressa as a first treatment over chemotherapy. "This is a proof of concept," says Sequist. "We were trying to see if personalized medicine or genetically driven cancer therapy was feasible."